Extracellular Vesicle-Mediated Precision Delivery of Paclitaxel Activates Mitophagy to Promote Repair after Spinal Cord Injury

Spinal cord injury (SCI) is a debilitating disorder characterized by intricate pathological processes that result in severe motor and sensory deficits. Existing therapeutic approaches remain insufficient to achieve comprehensive functional restoration, indicating the necessity of alternative treatment strategies. In this study, an advanced nanoparticle-based drug delivery system was established using extracellular vesicles (EVs) modified with a matrix metalloproteinase (MMP)-responsive peptide, ACPP, to achieve the targeted delivery of paclitaxel (PTX). The ACPP-EVs@PTX formulation integrates the drug loading capacity of EVs, the lesion-targeting capability conferred by ACPP, and the neuroprotective properties of PTX. Enhanced accumulation of PTX at the SCI lesion site was achieved, accompanied by a reduction in the off-target distribution. Both in vitro and in vivo experiments demonstrated marked therapeutic efficacy of ACPP-EVs@PTX through modulation of the SCI microenvironment, including stimulation of angiogenesis, attenuation of inflammatory responses, alleviation of oxidative stress, and promotion of axonal regeneration. In addition, the activation of PINK1-Parkin-mediated mitophagy was observed, leading to improved mitochondrial function and enhanced neuronal repair. Behavioral evaluations further confirmed significant recovery of neurological function, supporting the translational potential of this multitarget, synergistic therapeutic strategy. Collectively, this work establishes an integrated therapeutic strategy for spinal cord repair and supports its translational potential.